Hematocrit Control and Phlebotomy Reduction Seen with Rusfertide in PV — 52-Week Extension Data
But here’s the key takeaway: a weekly self-administered peptide, Rusfertide, sustained hematocrit control and lowered the need for phlebotomy over a full year in polycythemia vera (PV) patients, according to extended findings from the VERIFY phase 3 trial.
At the American Society of Hematology (ASH) 2025 Annual Meeting, hematologist-oncologist Andrew Kuykendall, MD, of Moffitt Cancer Center in Tampa, presented the updated results. He noted that among 147 participants who initially received rusfertide, demonstrated a durable response, and remained on the drug beyond 32 weeks, 61.9% were not eligible for phlebotomy at any point during the 52 weeks. Of 140 patients who crossed over from placebo to rusfertide at 32 weeks, 77.9% were not eligible for phlebotomy from weeks 40 to 52, up from 32.9% during the first 32 weeks. Across both groups, mean hematocrit stayed below 43%.
Rusfertide is a peptide mimic of hepcidin, the hormone that helps regulate iron. Although not yet FDA-approved for PV, the drug has demonstrated an ability to safely and consistently keep blood counts in a range that lowers cardiovascular risk and related symptoms or death if uncontrolled. It may also alleviate disease-related symptoms that current therapies can worsen.
PV arises from overproduction of red blood cells, leading to symptoms such as itch (pruritus), night sweats, trouble concentrating, and potentially severe fatigue. Kuykendall highlighted that maintaining hematocrit under 45% has been linked with a reduced risk of major cardiovascular events. Traditionally this is achieved with regular therapeutic phlebotomy, sometimes supplemented by cytoreductive therapies.
However, repeated phlebotomy can deplete iron stores, tether patients to healthcare visits, and is not always well tolerated. Real-world data also indicate phlebotomy is rarely optimized in practice, leaving many patients at subgoal levels.
Methods and Key Findings
The VERIFY trial’s 32-week data, released in June 2025, showed that rusfertide reduced the average number of phlebotomies to 0.5 per patient versus 1.8 for those on placebo (P < .0001). For a key secondary endpoint, 62.6% of rusfertide patients kept hematocrit below 45% compared with 14.4% in the placebo group (P < .0001).
In the extended analysis from weeks 32 to 50, the median time to first phlebotomy was not reached in either treatment group, indicating durable responses. Quality of life measures also showed sustained improvements: PROMIS Fatigue SF-8a and MFSAF TSS7 scores remained better than baseline in the early rusfertide group through weeks 32–50. Among those treated with rusfertide (n = 285), the most common treatment-emergent adverse events were injection-site reactions (47.4%), anemia (25.6%), and fatigue (19.6%), most of which were mild to moderate (grade 1–2).
From weeks 0–32, fatigue occurred in 15.9% of the rusfertide group and 15.8% of the placebo group; from weeks 32–52, these rates were 9.0% and 9.3%, respectively.
Serious adverse events occurred in 8.1% of rusfertide-treated patients. Non-PV malignancies occurred in 2.1% of rusfertide patients and 5.5% of placebo patients from weeks 0–32, with 2.2% of all participants experiencing such events from weeks 32–52.
Given PV patients’ higher baseline risk for non-PV cancers, monitoring for second cancers, including non-melanoma skin cancers that PV therapies can influence, remains important, Kuykendall noted. Injection-site reactions tended to improve over time.
Thrombotic events occurred in two patients within the rusfertide cohort (one during the initial period, one during the extension).
Expert Opinions and Context
During discussion, an audience member asked about combining rusfertide with cytoreductive therapies. Kuykendall suggested that this class of agent could enable dose optimization of existing cytoreductive drugs, potentially allowing lower, better-tolerated dosages while achieving phlebotomy independence.
Hobbs added that the extension data show durable responses without new safety concerns. She emphasized that rusfertide could become the first in a new generation of PV treatments aiming to eliminate the need for therapeutic phlebotomy, a burden that is logistically challenging and time-consuming for patients.
What’s Next?
The VERIFY study continues, with discussions at ASH indicating that FDA approval is being pursued. Protagonist Therapeutics funded the study. Relationships between the investigators and industry partners were disclosed and vary among authors.
Controversy and discussion prompts:
- If rusfertide proves durable and broadly safe, should it replace phlebotomy as the standard first-line approach to hematocrit control in PV, or should it be reserved for patients who do not tolerate phlebotomy well?
- How might concurrent cytoreductive therapy influence long-term outcomes and quality of life for PV patients on rusfertide?
- Given the potential for non-PV malignancies in PV populations, how should long-term safety monitoring be structured as new therapies emerge?
Would you support moving toward therapies that could completely spare PV patients from regular phlebotomy, or do you prefer maintaining phlebotomy as a core management tool while adding new drugs? Share your thoughts in the comments.
